Multiple Mechanisms Controlling Uterine Function: Editorial to Special Issue "Molecular Mechanisms of Uterine Receptivity for Embryo Implantation".

Uterine (endometrial) receptivity is the ability of the endometrium to successfully attach to the embryo, to promote its implantation, to nourish it and keep it alive [...].

Mitochondria in Human Fertility and Infertility.

In human spermatozoa and oocytes (and their surrounding granulosa cells), mitochondria carry out important functions relating to human fertility and infertility. Sperm mitochondria are not transmitted to the future embryo, but are closely related to the generation of energy needed for sperm movement, capacitation, and acrosome reactions, as well as for sperm-oocyte fusion. On the other hand, oocyte mitochondria produce energy required for oocyte meiotic division and their abnormalities can thus cause oocyte and embryo aneuploidy. In addition, they play a role in oocyte calcium metabolism and in essential epigenetic events during the oocyte-to-embryo transition. They are transmitted to the future embryos and may thus cause hereditary diseases in the offspring. Due to the long life span of the female germ cells, the accumulation of mitochondrial DNA abnormalities often causes ovarian aging. Mitochondrial substitution therapy is the only way of dealing with these issues nowadays. New therapies based on mitochondrial DNA editing are under investigation.

Complementarity between Early Embryogenesis and Uterine Receptivity: Toward Integrative Approach to Female Infertility Management. Editorial to the Special Issue "Molecular Mechanisms of Human Oogenesis and Early Embryogenesis".

Two highly relevant papers were recently been published in the Special Issue of Molecular Sciences entitled "Molecular Mechanisms of Human Oogenesis and Early Embryogenesis" [...].

Risk of endometrial cancer in asymptomatic postmenopausal women in relation to ultrasonographic endometrial thickness: systematic review and diagnostic test accuracy meta-analysis.

OBJECTIVE: This study aimed to evaluate the risk of endometrial carcinoma and atypical endometrial hyperplasia in asymptomatic postmenopausal women concerning the endometrial thickness measured by stratified threshold categories used for performing subsequent endometrial sampling and histologic evaluation. DATA SOURCES: MEDLINE, Scopus, ClinicalTrials.gov, SciELO, Embase, the Cochrane Central Register of Controlled Trials, LILACS, conference proceedings, and international controlled trials registries were searched without temporal, geographic, or language restrictions. STUDY ELIGIBILITY CRITERIA: Studies were selected if they had a crossover design evaluating the risk of atypical endometrial hyperplasia and endometrial carcinoma in postmenopausal asymptomatic women and calculated the diagnostic accuracy of transvaginal ultrasonography thresholds (at least 3.0 mm) confirmed by histopathologic diagnosis. METHODS: This was a systematic review and diagnostic test accuracy meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy and Synthesizing Evidence from Diagnostic Accuracy Tests guidelines. Endometrial thickness thresholds were grouped as follows: from 3.0 to 5.9 mm; between 6.0 and 9.9 mm; between 10.0 and 13.9 mm; and ≥14.0 mm. Quality assessment was performed using the Quality Assessment Tool for Diagnostic Accuracy Studies 2 tool. Publication bias was quantified using the Deek funnel plot test. Coprimary outcomes were the risk of atypical endometrial hyperplasia or endometrial carcinoma according to the endometrial thickness and diagnostic accuracy of each threshold group. RESULTS: A total of 18 studies provided the data of 10,334 women who were all included in the final analysis. Overall, at an endometrial thickness threshold of at least 3.0 mm, the risk of atypical endometrial hyperplasia or endometrial carcinoma was increased 3-fold relative to women below the cutoff (relative risk, 3.77; 95% confidence interval, 2.26-6.32; I2=74%). Similar degrees of risk were reported for thresholds between 3.0 and 5.9 mm (relative risk, 5.08; 95% confidence interval, 2.26-11.41; I2=0%), 6.0 and 9.9 mm (relative risk, 4.34; 95% confidence interval, 1.68-11.23; I2=0%), 10.0 and 13.9 mm (relative risk, 4.11; 95% confidence interval, 1.55-10.87; I2=86%), and ≥14.0 mm (relative risk, 2.53; 95% confidence interval, 1.04-6.16; I2=78%) with no significant difference among subgroups (P=.885). Regarding diagnostic accuracy, the pooled sensitivity decreased from thresholds below 5.9 mm (relative risk, 0.81; 95% confidence interval, 0.49-0.85) to above 14.0 mm (relative risk, 0.28; 95% confidence interval, 0.18-0.40). Furthermore, the specificity increased from 0.70 (95% confidence interval, 0.61-0.78) for endometrial thickness between 3.0 and 5.9 mm to 0.86 (95% confidence interval, 0.71-0.94) when the endometrial thickness is ≥14.0 mm. For 3.0 to 5.9 mm and 10.0 to 13.9 mm thresholds, the highest diagnostic odds ratios of 10 (95% confidence interval, 3-41) and 11 (95% confidence interval, 2-49), with areas under the curve of 0.81 (95% confidence interval, 0.77-0.84) and 0.82 (95% confidence interval, 0.79-0.86), respectively, were retrieved. The summary point analysis revealed that the 3.0 to 5.9 mm cutoff point was placed higher in the summary receiver operator curve space than the other subgroups, indicating increased endometrial carcinoma or atypical endometrial hyperplasia diagnosis using these cutoffs. CONCLUSION: Both low and high endometrial thickness thresholds in postmenopausal asymptomatic women seem equally effective in detecting endometrial carcinoma and atypical endometrial hyperplasia. However, although using a 3.0 to 5.9 mm cutoff results in a lower specificity, the offsetting improvement in sensitivity may justify using this cutoff for further endometrial evaluation in patients with suspected endometrial malignancy.

Cyclic Adenosine Monophosphate: A Central Player in Gamete Development and Fertilization, and Possible Target for Infertility Therapies.

Human infertility, of both male and female origin, is often caused by the deficient response of the testis and the ovary to hormonal stimuli that govern sperm and oocyte development and fertilization. The effects of hormones and other extracellular ligands involved in these events are often mediated by G-protein-coupled receptors that employ cyclic adenosine monophosphate (cAMP) as the principal second messenger transducing the receptor-generated signal to downstream elements. This opinion article summarizes the actions of cAMP in sperm and oocyte development and fertilization, leading to therapeutic actions targeting cAMP metabolism to alleviate human male and female infertility.

Patient-tailored reproductive health care.

Patient-tailored reproductive health care represents an important challenge for the current practice of infertility prevention, diagnosis and treatment. This approach is based on the concept of precision medicine, taking into account genetic, epigenetic, metabolic and lifestyle characteristics of each individual patient. Even though this goal is still far from being wholly achieved, some aspects can already be put into practice nowadays. Personalization can be based on a comprehensive analysis and synthesis of the patients' personal and familial history, taking into account outcomes of previous assisted reproduction technique (ART) attempts, if available, and confronting these data with the past and the latest clinical and laboratory examination outcomes. As to the male fertility status, there is an urgent need for the inclusion of an accurate diagnostic workup of infertile men leading to the choice of the most adequate follow-up for each particular pathological condition. The follow-up of women who have become pregnant as a result of the ART attempt has also to be personalized. This should be done taking into account both the basic data extracted from the patient's file and those derived from the experience gathered during the latest attempt. Last but not least, the individual condition of each couple has to be taken into account when counseling the patients as to the urgency of the actions to be taken to resolve their fertility problem.

Molecular Clues to Understanding Causes of Human-Assisted Reproduction Treatment Failures and Possible Treatment Options.

More than forty years after the first birth following in vitro fertilization (IVF), the success rates of IVF and of IVF-derived assisted reproduction techniques (ART) still remain relatively low. Interindividual differences between infertile couples and the nature of the problems underlying their infertility appear to be underestimated nowadays. Consequently, the molecular basis of each couple's reproductive function and of its disturbances is needed to offer an individualized diagnostic and therapeutic approaches to each couple, instead of applying a standard or minimally adapted protocols to everybody. Interindividual differences include sperm and oocyte function and health status, early (preimplantation) embryonic development, the optimal window of uterine receptivity for the implanting embryo, the function of the corpus luteum as the main source of progesterone production during the first days of pregnancy, the timing of the subsequent luteoplacental shift in progesterone production, and aberrant reactions of the uterine immune cells to the implanting and recently implanted embryos. In this article, the molecular basis that underlies each of these abnormalities is reviewed and discussed, with the aim to design specific treatment options to be used for each of them.

Application of a new ultrasound criterion for the diagnosis of polycystic ovary syndrome.

Objective: To define which ultrasound criteria could replace the classic Rotterdam criteria as the best indicator of the risk of developing endocrine-metabolic changes in women with polycystic ovary syndrome (PCOS). Materials and methods: This multicenter cross-sectional study included 200 women with PCOS and one control group of 111 women without PCOS. The primary outcomes to be considered were follicular count, hirsutism, total testosterone levels, free androgen index (FAI), and insulin sensitivity (HOMA-IR), and the secondary outcome was the anti-Müllerian hormone (AMH) level. Results: The main finding in this study points toward a different ultrasound criterion-23 or more follicles of any size in at least one ovary, which is postulated as an alternative to the classic criterion described in the Rotterdam consensus. This criterion correlates better with the other two PCOS criteria and also identifies women at increased risk of hirsutism (Ferriman-Gallwey score: 6.08 ± 3.54 vs. 4.44 ± 3.75, p < 0.0001), total testosterone levels (2.24 ± 0.298 vs. 1.42 ± 1.530, p = 0.0001), FAI (4.85 ± 0.83 vs. 2.12 ± 1.93, p < 0.001), and insulin resistance (HOMA-IR: 1.74 ± 0.182 vs. 1.504 ± 0.230, p = 0.001) more accurately. Regarding AMH, large differences in their mean values were observed between the groups (7.07 vs. 4.846 ng/ml, p = 0.000). However, these differences depended on age. Conclusion: The ovarian ultrasound examination with 23 or more follicles of any size in any of the ovaries constitutes a powerful tool to accurately diagnose PCOS and to associate it with metabolic-endocrine processes such as hyperandrogenism and insulin resistance.

Control of Maternal-to-Zygotic Transition in Human Embryos and Other Animal Species (Especially Mouse): Similarities and Differences.

Maternal-to-zygotic transition (MZT) of the control of early post-fertilization development is a key-event conditioning the fate of the future embryo, fetus and newborn. Because of the relative paucity of data concerning human embryos, due to ethical concerns and the poor availability of human embryos donated for research, most data have to be derived from animal models, among which those obtained using mouse embryos are most prevalent. However, data obtained by studies performed in non-mammalian specie can also provide useful information. For this reason, this review focuses on similarities and differences of MZT control mechanisms in humans and other species, with particular attention to the mouse. A number of molecular pathways controlling MZT in mice and humans are compared, pointing out those that could be at the origin of further focused experimental studies and the development of new diagnostic tools based on the translational medicine principles. Data concerning possible candidate molecules to be included in these studies are identified.

Use of pentoxifylline during ovarian stimulation to improve oocyte and embryo quality: A retrospective study.

OBJECTIVE: This study aims to investigate if the administration of pentoxifylline during ovarian stimulation have an impact on the quantity and quality of oocytes recovered for in vitro fertilization (IVF), the quality of zygotes and embryos resulting from IVF, the serum estradiol and progesterone concentrations, the endometrial thickness and pregnancy outcomes after embryo transfer. METHODS: Retrospective crossover study including 18 women with recurrent implantation failur, defined as having a history of at least two consecutive cycles of implantation failure and 25-45 years of age at the time of embryo transfer. Pentoxifylline was added during their following IVF attempt aiming to improve endometrial function. Oocyte, zygote and embryo quality, serum estradiol and progesterone concentrations, endometrial thickness and IVF outcomes were compared between the two sequential attempts. RESULTS: Compared to the first attempt, the outcomes of the second attempt, with the addition of pentoxifylline administration, resulted in higher numbers of total and mature oocytes, better oocyte, zygote and embryo quality, higher serum estradiol concentrations, thicker endometrium and better clinical IVF outcomes. CONCLUSIONS: The administration of pentoxifylline during ovarian stimulation seems to improve IVF outcomes, not only by the generating a thicker endometrial lining, but also by producing a higher number of oocytes, with better oocyte, zygote and embryo quality, and higher serum estradiol concentrations.

The role of hysteroscopy in reproductive surgery: Today and tomorrow.

During the last decades, the number of couples with reproductive issues has substantially increased. Many different factors are implicated in reproductive failure, including uterine factors. Endometrial pathologies, such as endometrial polyps, hyperplasia, endometritis, and Mullerian anomalies, can also hinder embryo implantation. Hysteroscopy remains the gold standard for the evaluation and treatment of intrauterine pathology. Over the last few years, advances in hysteroscopic instrumentations and surgical techniques have significantly evolved, the refinement in technology, miniaturization of instruments, and improved image quality have rendered hysteroscopy a more patient and user-friendly procedure that has enhanced its use in reproductive medicine. Nowadays, hysteroscopy is essential in the evaluation and treatment of women with infertility. This article underscores the major technological breakthroughs achieved over the last few years with emphasis on the role of artificial intelligence, augmented reality, and 3D hysteroscopy, which can set new benchmarks in hysteroscopy applied to reproductive medicine.

Melatonin: highlighting its use as a potential treatment for SARS-CoV-2 infection.

Numerous pharmaceutical drugs have been repurposed for use as treatments for COVID-19 disease. These drugs have not consistently demonstrated high efficacy in preventing or treating this serious condition and all have side effects to differing degrees. We encourage the continued consideration of the use of the antioxidant and anti-inflammatory agent, melatonin, as a countermeasure to a SARS-CoV-2 infection. More than 140 scientific publications have identified melatonin as a likely useful agent to treat this disease. Moreover, the publications cited provide the rationale for the use of melatonin as a prophylactic agent against this condition. Melatonin has pan-antiviral effects and it diminishes the severity of viral infections and reduces the death of animals infected with numerous different viruses, including three different coronaviruses. Network analyses, which compared drugs used to treat SARS-CoV-2 in humans, also predicted that melatonin would be the most effective agent for preventing/treating COVID-19. Finally, when seriously infected COVID-19 patients were treated with melatonin, either alone or in combination with other medications, these treatments reduced the severity of infection, lowered the death rate, and shortened the duration of hospitalization. Melatonin's ability to arrest SARS-CoV-2 infections may reduce health care exhaustion by limiting the need for hospitalization. Importantly, melatonin has a high safety profile over a wide range of doses and lacks significant toxicity. Some molecular processes by which melatonin resists a SARS-CoV-2 infection are summarized. The authors believe that all available, potentially beneficial drugs, including melatonin, that lack toxicity should be used in pandemics such as that caused by SARS-CoV-2.

Virtual sonographic hysteroscopy in assisted reproduction: A retrospective cost-effectiveness analysis.

OBJECTIVE: To analyze the cost-effectiveness of virtual sonographic hysteroscopy (VSH) performed before in vitro fertilization (IVF) (Scenario 1), frozen embryo transfer (Scenario 2), and oocyte donation (Scenario 3) attempts. METHODS: A retrospective analysis of data extracted from patients' files was conducted. Before undergoing the assigned treatment, VSH was offered to all patients. Cost-effectiveness was calculated on the basis of cost per live birth. The total cost was compared with a control group of patients who declined to have hysteroscopy before their treatment. RESULTS: A total of 292 women were involved. Virtual sonographic hysteroscopy was performed in 192 women. Conventional operative hysteroscopy was subsequently required in 34 of them (17.7%). Subsequent assisted reproduction attempts resulted in live birth in 111 women-34/69 (49.3%), 35/69 (50.7%), and 42/54 (77.8%) in Scenarios 1, 2, and 3, respectively. This compared favorably with 100 women who declined VSH, with live birth achieved in 15/39 (38.5%), 14/37 (37.8%), and 15/24 (62.5%) in Scenarios 1, 2, and 3, respectively. The overall cost-effectiveness of VSH compared favorably with straightforward treatment performed without this test. CONCLUSION: The overall cost-effectiveness of treatment attempts carried out after previous VSH compared favorably with straightforward treatment performed without this test.

Double HCG trigger improves recovery of oocytes in women with a paucifollicular response to ovarian stimulation: A pilot study.

OBJECTIVE: To examine whether adding a second HCG trigger, 12.5 h after the first (36.5 h before ovarian puncture), can facilitate recovery of oocytes in women with a paucifollicular response to ovarian stimulation. METHODS: A total of 85 women aged 35-42 years, with a paucifollicular response to ovarian stimulation and who had experienced a total failure of oocyte recovery after the standard HCG ovulation trigger 36.5 h before ovarian puncture, were subsequently treated by the same protocol but with the addition of a second HCG trigger 12.5 h later. The recovered oocytes were inseminated by intracytoplasmic sperm injection (ICSI) and all available embryos were transferred 3 days later. RESULTS: The double trigger enabled recovery of cumulus oophorus cells from most of the follicles in the women who experienced failure of total recovery of oocytes after a single trigger. Fifteen patients became pregnant, and no signs of ovarian hyperstimulation syndrome were observed. Nine women delivered a healthy child. CONCLUSION: In women aged 35-42 years with a paucifollicular response to ovarian stimulation, a double HCG trigger appears to improve the rate of oocyte recovery. The conclusion of this pilot study needs to be confirmed by larger prospective trials.

Towards Personalized Antioxidant Use in Female Infertility: Need for More Molecular and Clinical Studies.

Treatment with antioxidants is increasingly used to slow down aging processes in different organs of the human body, including those implicated in female fertility. There is a plethora of different natural, synthetic or semi-synthetic medicines available on the market; most of them can be purchased without medical prescription. Even though the use of antioxidants, even under conditions of auto-medication, was shown to improve many functions related to female infertility related to oxidative stress, the lack of medical control and supervision can lead to an overmedication resulting in an opposite extreme, reductive stress, which can be counterproductive with regard to reproductive function and produce various adverse health effects in general. This paper reviews the current knowledge relative to the effects of different antioxidants on female reproductive function. The persisting gaps in this knowledge are also highlighted, and the need for medical supervision and personalization of antioxidant prescription is underscored.

Toward Molecular Medicine in Female Infertility Management: Editorial to the Special Issue "Molecular Mechanisms of Human Oogenesis and Early Embryogenesis".

Female infertility is the main reason for involuntary childlessness nowadays [...].

Hysteroscopic endometrial biopsy: from indications to instrumentation and techniques. A call to action.

During the last twenty years, the diagnostic approach to endometrial pathology has radically evolved. For over a century, intrauterine blind biopsy techniques were considered the gold standard procedure for the histopathological diagnosis of intrauterine diseases. The advent of hysteroscopy, which made it possible to directly visualize the uterine cavity, and the subsequent miniaturization of the instruments allowing its use in the office setting without anesthesia are considered game-changers. To date, it is feasible to retrieve a targeted eye specimen of endometrial tissue with little or no discomfort for the patient in the office setting. To pursue this aim, several technological upgrades have improved the diagnostic accuracy of hysteroscopic endometrial biopsy. In this paper we provide an up-to-date review of the latest evidence regarding indications, instrumentations, and techniques for hysteroscopic endometrial biopsy, to help the operator in providing an adequate endometrial sampling for histopathological analysis.